THE ANATOMICAL RECORD 297:16–25 (2014)

Tissue Engineering in Periodontal Tissue TAKANORI IWATA,1,2 MASAYUKI YAMATO,1 ISAO ISHIKAWA,1 TOMOHIRO ANDO,2 AND TERUO OKANO1* 1 Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan 2 Department of Oral and Maxillofacial Surgery, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan

ABSTRACT Periodontitis, a recognized disease worldwide, is bacterial infectioninduced inflammation of the periodontal tissues that results in loss of alveolar bone. Once it occurs, damaged tissue cannot be restored to its original form, even if decontaminating treatments are performed. For more than half a century, studies have been conducted to investigate true periodontal regeneration. Periodontal regeneration is the complete reconstruction of the damaged attachment apparatus, which contains both hard tissue (alveolar bone and cementum) and soft tissue (periodontal ligament). Several treatments, including bone grafts, guided tissue regeneration with physical barriers for epithelial cells, and growth factors have been approved for clinical use; however, their indications and outcomes are limited. To overcome these limitations, the concept of “tissue engineering” was introduced. Combination treatment using cells, growth factors, and scaffolds, has been studied in experimental animal models, and some studies have been translated into clinical trials. In this review, we focus on recent progressive tissue engineering studies and discuss future perspectives on periodontal C 2013 Wiley Periodicals, Inc. regeneration. Anat Rec, 297:16–25, 2014. V

Key words: periodontal tissue; periodontal regeneration; periodontal ligament; bone; cementum; stem cells; cytotherapy; clinical trials

Periodontitis is a global disease that destroys the tooth-supporting attachment apparatus, which consists of alveolar bone, cementum, and periodontal ligament. Recent studies have reported numerous associations between periodontitis and systemic diseases, such as cardiovascular disease (de Oliveira et al., 2010) and diabetes mellitus (Lalla and Papapanou, 2011), as well as a higher risk of preterm low birth-weight babies (Offenbacher et al., 1996). Furthermore, research has recently shown that Bisphosphonate-Related Osteonecrosis of the Jaws (BRONJ) is associated with severe periodontitis (Vescovi et al., 2011). Consequently, periodontal treatment may not only contribute to oral hygiene but also improve systemic conditions (Seymour et al., 2007). Conventional treatments such as scaling, root-planing, and surgical cleaning are currently performed to remove the bacteria and contaminated tissue. However, these C 2013 WILEY PERIODICALS, INC. V

procedures frequently result in the formation of weak attachment called a “long junctional epithelium,” LJE, (Caton et al., 1980). In addition, these conventional

Grant sponsor: The Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. Grant sponsor: Creation of innovation centers for advanced interdisciplinary research areas Program in the Project for Developing Innovation Systems “Cell Sheet Tissue Engineering Center (CSTEC).” *Correspondence to: Teruo Okano, Ph.D., Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. Fax: 181333596046. E-mail: [email protected] Received 13 September 2013; Accepted 13 September 2013. DOI 10.1002/ar.22812 Published online 2 December 2013 in Wiley Online Library (



Fig. 2. Higher magnification of the palatal side of Fig. 1 (natural periodontal tissue). Sections were stained with Azan (left) or hematoxylin– eosin (right). D: dentin, C: cementum, PDL: periodontal ligament, B: alveolar bone (bars, 50 mm).

Fig. 1. Photomicrograph of canine maxillary premolar. Periodontal defect was mechanically created in the left (buccal) side of the teeth (5 mm in height). Six week after the cell transplantation, the sample was decalcified in Plank-Rychro solution for 6 weeks, routinely processed into 6-mm thick paraffin-embedded sections, and stained with Azan. This picture shows both natural periodontal tissue in the right (palatal) side and spontaneously regenerated tissue in the left (buccal) side simultaneously. G: gingiva, D: dentin, B: alveolar bone, P: dental pulp, NB: newly-formed bone (bar, 1 mm).

procedures cannot restore the periodontal tissue to its original form, and the decrease in bone height and gingival recession usually cause aesthetic and functional problems. Several regenerative procedures have already been introduced to clinical practice to overcome these problems, including bone grafts, guided tissue regeneration, and enamel matrix derivative. However, the outcomes of these procedures have limited success and have poor clinical predictability (Esposito et al., 2009). Therefore, research has turned to investigating stem cellbased approaches for periodontal regeneration [see in review (Ishikawa et al., 2009)]. “Tissue engineering,” a concept proposed by Langer and Vacanti, is widely accepted in the field of regenerative medicine to create replacement tissues using a combination of cells, scaffolds, and growth factors (Langer

Fig. 3. Higher magnification of the buccal side of Fig. 1 (spontaneous healing model). The most coronal area of newly formed periodontal tissue. Note newly formed cementum covering the rough surface of dentin. Arrowhead shows the coronal extention of new cementum. In this case, well-oriented fibers between cementum to alveolar bone was not observed (bar, 50 mm).

and Vacanti, 1993). However, there are limitations to this concept; grafts may be rejected as a result of inflammation caused by scaffold degradation, necrosis, or unstable transplanted cells (Yang et al., 2005). Several technologies using new biomaterials are being introduced to overcome these limitations (Williams, 2009). In this review, we focus on recent studies involving tissue engineering and regenerative medicine using biomaterials in the periodontal field.

PERIODONTAL TISSUE Periodontal tissue consists of four component structures: alveolar bone, periodontal ligament, cementum,



cially in anterior teeth (Fig. 4c). If periodontitis is left untreated, the attachment apparatus is completely destroyed resulting in tooth mobility and loss. The purpose of conventional periodontal therapies, such as scaling, root planing, and periodontal surgery, is to remove the bacterial pathogens and infected granulation tissues surrounding the teeth. These procedures can halt the disease process, but they cannot restore the tissue to its original form. Additionally, the treatments may result in the formation of an LJE; thus, patients tend to relapse without maintenance therapies (Axelsson and Lindhe, 1981). The final goal of periodontal regeneration is to reform the lost tissue and restore to its original form (bone structures with well-oriented periodontal ligament anchoring to dental cementum).


Fig. 4. (a) Inflammation is observed in anterior teeth. Arrowheads indicate gingival rubor and swelling. (b) Severe periodontitis. Fiftyyear-old male, who did not go to dental office for 30 years, complained tooth mobility. Radiographic examination (right panel) indicated bone resorption beyond the apex of the first molar (arrowhead). (c) Aesthetic problems after periodontal treatment. Although deep pockets were eliminated by conventional therapies, aesthetic, and functional problems are still remaining due to gingival recession and flaring out.

and gingiva (Figs. 1–3). Specifically, alveolar bone, periodontal ligament, and cementum are called the “attachment apparatus” and are the target tissues for periodontal regeneration (Fig. 2).

Pathogenesis and Treatment of Periodontal Disease “Gingivitis” or gingival inflammation is initiated and promoted by the accumulation of dental plaque (Fig. 4a). If the inflammation is localized within the gingiva, proper plaque control can restore a healthy condition. However, once the inflammation and the host immune response expand to the adjacent periodontal tissues (alveolar bone, cementum, and periodontal ligament), connective tissues, and bone become permanently damaged. This spread of inflammation is called “periodontitis,” and spontaneous healing is not expected (Fig. 4b). Although decontaminating procedures can be performed, the height of bone will not improve. Moreover, gingival recessions create aesthetic issues, espe-

Bone graft regeneration is still somewhat controversial; bone grafts may not always regenerate true periodontal tissue with well-oriented fibers anchoring the cementum to the alveolar bone (Mellonig, 1992). Histological analyses have revealed that LJE between the alveolar bone and root surface often migrate apically. In addition, root resorption and ankylosis are occasionally observed (Table 1). Clinical studies have shown that the gain of bone height is 3.0 mm irrespective of the type of bone graft material (Mellonig, 1992). The gold standard for bone grafting is autologous bone, which is capable of osteogenesis, osteoinduction, and osteoconduction. For these grafts, a portion of bone is taken from a healthy site of the patient receiving the graft. The advantage of autologous bone is that it inherently has the vital structures of bone tissue and contains cells, minerals, and proteins. The disadvantages of autologous bone grafts are the patient morbidities at the removal sites and limited amount of bone that can be harvested. As a result of these disadvantages, many allogeneic bone grafts and xenograft materials have been investigated and approved and are commercially available (Miron and Zhang, 2012). However, clinicians must consider the potential risks of disease transmission, rejection, and resorption when using these grafts. There are two types of allografts: demineralized freeze-dried bone allografts and freeze-dried bone allografts. Both of these types of allografts are chemically pretreated, retaining osteoinductive proteins such as BMPs and TGF-bs, to enhance the osteoinduction of endogenous mesenchymal stromal cells. It is thought that the process of demineralization enhances the release of inherent growth factors, such as BMPs (Urist, 1965). Xenografts are derived from non-human species, such as bovine, porcine, or equine animals. They are usually sintered and chemically pretreated to remove their antigenicity. The advantage of these products is that the shape of the gragt can be retained, because the resorption of these materials is relatively slow. Although they are only capable of osteoconductivity, the safety and efficacy of these products have been proved clinically (Camelo et al., 1998; Richardson et al., 1999). Because of the risks associated with allograft and xenograft materials, researchers have also investigated



TABLE 1. Bone graft materials

Autologous bone

Allogeneic bone

Demineralized freeze-dried bone allograft (DFDBA) Freeze-dried bone allograft (DFDBA)

Xenogeneic bone Artificial materials

Sintered hydroxyapatite (HA) b-tricalcium phosphate (TCP) Natural products (coral, citosan etc.)



Osteogenic, osteoinductive and osteoconductive no immunological rejection living cells and matrices Osteoinudctive and osteoconductive

Morbidity at donor sites amount of bone volume is limited rapid absorption

Osteoinudctive and osteoconductive Osteoconductive Osteoconductive Osteoconductive Osteoconductive, low immunological rejection

Potential of infection and immunological rejection Potential of infection and immunological rejection Potential of infection and immunological rejection Slow resorption or non-resorbable Slow resorption or non-resorbable Rapid resorption Slow resorption or non-resorbable

Tissue engineering in periodical tissue

synthesized graft materials, including polymer and inorganic composite grafts, to regenerate bone [see in review (Rezwan et al., 2006)]. Specifically hydroxyapatite (HA) and b-tricalcium phosphate (b-TCP) have been studied in human periodontal defect models. Although synthesized materials are only osteoconductive (not osteogenic or osteoinductive), they can successfully restore bone defects if the environment is favorable. Recently, moldable in situ hardening polylactide-coated TCP has been developed and applied to repair bone defects in rabbits; the results showed good biocompatibility (Schmidlin et al., 2013). Natural products, such as coral, have also been investigated for bone grafting because their structures are similar to those of bone (Damien and Revell, 2004). Like synthetic materials, natural products are only osteoconductive, but they are cost-effective and considered to pose no risk to human health.

Physical Barriers for Epithelial Tissue In the past, it was predicted that the periodontal ligament tissue contains the cells responsible for periodontal regeneration (Melcher, 1976); recently, such multipotent cells have been identified in periodontal tissue (Seo et al., 2004; Gay et al., 2007; Iwata et al., 2010). In the 1980’s, physical barriers were introduced into periodontal surgeries to eliminate epithelial downgrowth, and selective proliferation of mesenchyme derived cells was enhanced (Nyman et al., 1982). Physical barriers have been widely employed in clinical practices, but this procedure involves technically difficult steps and potential complications, such as exposure of the barrier or infection. Various barrier membranes have been developed and are commercially available.

Enamel Matrix Derivatives (EMD) R ), a EMD (commercially available as EMDOGAINV mixture of porcine immature enamel extracts, has been showed to effectively treat infrabony periodontal

defects (Heijl et al., 1997). A meta-analysis (eight trials) showed that EMD-treated sites displayed statistically significant improvements compared with sites treated with flap surgery (Esposito et al., 2009). The main component of EMD is amelogenin, a majority of enamel proteins, and amelogenin is believed to possess the properties needed to regenerate periodontal tissue because the expression of amelogenin was observed in developing dental root (Hammarstrom, 1997). In addition to enamel matrix proteins, several studies have demonstrated that EMD contains small amount of growth factors, such as BMPs (Iwata et al., 2002; Johnson et al., 2009) and TGF-b1 (Suzuki et al., 2005), explaining the complex effects of EMD. A particularly interesting study found that propylene glycol alginate (PGA), the vehicle of EMD, has antibacterial properties, suggesting that the combination of EMD and PGA enhances not only periodontal (Sculean et al., 2001) but also epithelial wound healing (Mirastschijski et al., 2004; Al-Hezaimi et al., 2012).

Tissue Engineering Approaches for Periodontal Regeneration Growth Factors used for Periodontal Regeneration Combining growth factors and carriers (scaffolds) for periodontal regeneration has also been investigated. This concept of using a drug delivery system (DDS) was introduced to prolong the therapeutic effects of growth factors (Chen et al., 2009). In this section, the application of growth factors to periodontal defect models in large animals is reviewed.

Platelet-Derived Growth Factor (PDGF)-BB and Insulin-Like Growth Factor One (IGF-1) The combination of PDGF-BB and IGF-1 was the first reported use of growth factors for periodontal regeneration, and it was tested in a canine model (Lynch et al., 1989). A subsequent clinical trial also showed that this combination of growth factors in a methylcellulose vehicle was safe and



that it enhanced periodontal regeneration (Howell et al., 1997). Giannobile et al. demonstrated that PDGF-BB alone significantly stimulates periodontal regeneration, but that IGF-1 alone does not alter periodontal wound healing in a nonhuman primate model (Giannobile et al., 1996). A multicenter randomized controlled trial with 180 subjects enrolled in 11 clinical centers showed the safety and efficacy of PDGF-BB soaked in b-TCP matrix for the treatment of advanced periodontal osseous defects (Nevins et al., 2005, 2013). This product is commercially available R (Osteohealth, Shirley, NY). as GEM 21 SV Several types of carriers for sustained-releasing of PDGF-BB, including porous poly(L-lactide) membranes (Park et al., 1998), chitosan sponges (Park et al., 2000), chitosan/TCP sponges (Lee et al., 2000), and nanofibrous scaffolds (Wei et al., 2006), have been investigated, and their efficacies were confirmed.

Bone Morphogenetic Proteins (BMPs) and Transforming Growth Factor-bs (TGF-bs) The BMP/TGF-b signaling pathway mediates osteoblastic differentiation and in vivo bone formation; BMP2 in particular has been thoroughly studied for periodontal regeneration. Several carriers, including autologous blood and poly(D,L-lactide-co-glycolide) (PLGA) particles (Sigurdsson et al., 1995), PLGA and gelatin sponges (Kinoshita et al., 1997), and absorbable collagen sponges (ACS; Selvig et al., 2002), have been investigated. The combination of BMP2/ACS is commercially available as R bone graft (Medtronic, Minneapolis, MN); it is INFUSEV approved for bone augmentation for sinus lifting and implant dentistry, but not for periodontal osseous defects at this time. Other members of the BMP family, such as BMP-7/OP-1 (Giannobile et al., 1998; Ripamonti et al., 2001), BMP-12/GDF-7 (Wikesjo et al., 2004), BMP-14/ GDF-5 (Kwon et al., 2010; Lee et al., 2010), have also been investigated in large animal models, and their efficacies for periodontal regeneration were observed in all studies. A recent study compared the carriers, b-TCP and ACS, for BMP14/GDF5 delivery in a canine periodontal defect model (Kim et al., 2013). The authors observed that b-TCP was superior for new bone formation. Whether TGF-b1 directly enhances periodontal regeneration is still controversial (Tatakis et al., 2000); however, it has been reported that TGF-b1 induced endochondral bone formation (Serra et al., 1999). R Another study suggested that TGF-b3 in MatrigelV matrix (BD Biosciences, San Jose, CA) in combination with minced muscle tissue significantly enhanced the periodontal regeneration in class III furcation defects in P. ursinus (Ripamonti et al., 2009).

Basic Fibroblast Growth Factor (bFGF, known as FGF2) The use of bFGF, a growth factor that is already utilized clinically for wound healing in patients with intractable skin ulcers, has been investigated for bone formation and periodontal regeneration. Its efficacy on periodontal regeneration was demonstrated in beagles and nonhuman primates (Murakami et al., 1999, 2003; Takayama et al., 2001). A multicenter, randomized clinical trial was performed using a 3% hydroxypropyl

cellulose carrier (Kitamura et al., 2008, 2011); the results showed that bFGF was safe and effective for periodontal regeneration. Several bFGF carriers, including sandwich membranes of collagen sponge with bFGF-incorporated gelatin microsphere (Nakahara et al., 2003), collagen gel (Sato et al., 2004), and b-TCP (Oi et al., 2009; Anzai et al., 2010), have been investigated.

Brain-Derived Neurotrophic Factor (BDNF) Despite its name, BDNF is found in several tissues, even in PDL cells (Kurihara et al., 2003). The application of BDNF in combination with atelocollagen sponge stimulated the formation of new alveolar bone, cementum, and connective fibers; the fibers were inserted into the newly formed cementum and bone in a canine class III furcation defect model. BDNF also stimulated blood capillary formation (Takeda et al., 2005). A recent study claimed that scaffolds made from high-molecular-weight hyaluronic acid improved the regenerative capacity of BDNF in a canine periodontal defect model (Takeda et al., 2011).

Cytotherapy for Periodontal Regeneration Several types of mesenchyme-derived cells have been investigated for periodontal regeneration.

Periodontal Ligament-Derived Stem Cells (PDLSCs) or Multipotent Mesenchymal Stromal Cells (PDL-MSCs) Shi and colleagues isolated and investigated a population of multipotent cells from human PDL tissues, called PDLSCs, which possessed the ability to form all components of the attachment apparatus when they were subcutaneously transplanted with b-TCP/HA scaffolds in immunodeficient mice (Seo et al., 2004). When autologous PDLSCs seeded in a HA/TCP scaffold were transplanted into periodontal defects of miniature pigs, complete periodontal regeneration was observed (Liu et al., 2008). Further studies used temperature responsive culture dishes to create PDL-MSC sheets. Threelayered canine PDL-MSC sheets were fabricated using R , PGA Feltwoven polyglycolic acid (PGA) (NeoveilV Sheet Type, 0.15 mm in thickness: Gunze, Tokyo, Japan) and transplanted into the denuded root surface autologously, while bone defects were filled with porous b-TCP (Iwata et al., 2009; Tsumanuma et al., 2011). After healing, complete periodontal regeneration was observed in both studies. In addition, PDLSC sheets without bone graft materials can regenerate complete periodontal tissue in a canine furcation defect model (Figs. 5 and 6). A recent study suggested that the allogeneic transplantation of PDLSC sheets with HA/TCP was applicable to periodontal regeneration; its safety and efficacy were confirmed in a swine model (Ding et al., 2010).

Bone Marrow-derived MSCs (BM-MSCs) Bone marrow-derived MSCs are thought to be trophic and immunomodulatory, as well as multipotent (Caplan and Correa, 2011). In fact, MSCs have been utilized in



Fig. 5. Class II furcation defects were created surgically at mandibular first molar (a), and the osseous defects were filled with rubber base impression materials to induce inflammation (b). At the same time, premolars were extracted to make PDLSC sheets. Eight weeks after the first surgery (c), the transplantation of PDLSC sheets was

performed. Class II furcation defect (5 3 5 3 5 mm3) was recreated (e) after the removal of the impression material and inflamed tissues (d). Six PDLSC sheets (arrowheads) were transplanted without any other graft materials autologously (f).

numerous clinical trials for various diseases, including graft versus host disease, acute myocardial infarction, stroke, acute kidney failure, and tendonitis. Clinical trials using BM-MSCs with platelet-rich plasma (PRP) have also been conducted, and the results demonstrated that periodontal regeneration was successful (Yamada et al., 2006, 2013). Another group used BMMSCs combined with atelocollagen sponges; eleven patients received the transplantation in Japan, based on

results from previous canine studies (Kawaguchi et al., 2004; Hasegawa et al., 2006).

Periosteum-Derived Cell Sheets Cultured periosteum is considered a suitable source of cells for periodontal regeneration because it is capable of differentiating into the osteoblast lineage. In one study, periosteum cell sheet samples (5 3 5 mm) were



harvested from patients by scraping, and an explant culture was performed in each case. Coagulated PRP and porous HA granules were placed into the infrabony defects, and 6-week-cultured periosteum sheets were autologously transplanted in 15 patients (Yamamiya et al., 2008; Okuda et al., 2009). The results showed that the cultured periosteum sheets transplantation exhibited a statistically significant improvement in clinical attachment gain, vertical relative attachment gain, and radiographic infrabony defect fill as compared with the control.

Adipose-Derived Stem Cells (ADSCs) ADSCs are a useful source for cell transplantation therapy because they are abundant and easy to obtain. ADSCs mixed with PRP enhanced the periodontal regeneration in rats (Tobita et al., 2008). Another source reported that ADSCs in a fibrin gel scaffold enhanced periodontal regeneration at applied sites (Murakami, 2011).

Gingival Epithelial Cells and Fibroblasts Gingival epithelial sheets derived from autologous gingival tissues were developed and applied clinically as a treatment for chronic desquamative gingivitis (Okuda et al., 2004). The results showed that human cultured gingival epithelial sheets promoted gingival augmentation. Recently, an allogeneic cellular product named GINTUITTM (Organogenesis) was approved by the FDA and was expected to be commercially available in the summer of 2012 ( oral_regeneration/oral_regeneration.html). This product consists of allogeneic cultured keratinocytes and fibroblasts in bovine collagen. In a pivotal, multicenter, randomized, within-patient, controlled, open-label trial, McGuire et al. concluded that the product was a safe and effective therapy for augmenting the keratinized gingival zone (McGuire et al., 2011).


Fig. 6. Eight weeks after the transplantation, radiographic, and hisological analysis of the recipient site was performed. Bone-like structures were observed in CT analysis (a and b). Histological analysis revealed that the periodontal tissue was regenerated at the 2 mm lingual side from the buccal bone (c) (bar, 1 mm, Azan). Arrows indicate the bottoms of the defect.

In this review, recent tissue engineering approaches for treating periodontal regeneration were described. Because cells or growth factors alone are not sufficient for periodontal regeneration, great efforts have been made to optimize the biological and biophysical design of carriers or scaffolds. Initially, biodegradable polymers were investigated, but they were not successful because controlling the shape of implants is difficult owing to resorption, and inflammation occasionally occurred. Therefore, more recent clinical studies have often use collagen or b-TCP as a carrier/scaffold to retain the cells/growth factors because of the safety, costeffectiveness, osteoconductivity, and biocompatibility of these materials. Other studies also suggest that welldesigned polymers or synthetic materials can be applicable as carriers/scaffolds for periodontal treatment. For example, a biphasic scaffold composed of a fused deposition modeling scaffold (bone compartment) and an electrospun membrane (periodontal compartment) with PDL cell sheets regenerated true periodontal tissue in an athymic rat subcutaneous model (Vaquette et al., 2012). In terms of cells, mesenchyme- or neural crest-derived cells are the most common cell source for periodontal


regeneration, because periodontal tissue originates from dental cranial neural crest cells (Ishikawa et al., 2009). One recent study suggested that the transplantation of induced pluripotent stem (iPS) cells with combination use of silk scaffold and EMD enhanced periodontal regeneration in mice (Duan et al., 2011). Furthermore, allogeneic embryonic stem (ES) cells in a collagen membrane improved periodontal furcation defects in a porcine model (Yang et al., 2013). Although the safety and efficacy of ES/iPS cells have not yet been proved, they may become an alternative cell source for periodontal regeneration in the future (Egusa et al., 2012).

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Tissue engineering in periodontal tissue.

Periodontitis, a recognized disease worldwide, is bacterial infection-induced inflammation of the periodontal tissues that results in loss of alveolar...
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